title: Phase I study of ON 01910.Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors.
abstract: OBJECTIVE
  We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G(2)/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1).
  
  
  METHODS
  Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1.
  
  
  RESULTS
  Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose cohort (3,120 mg) was expanded to six assessable patients. Toxicities were skeletal, abdominal, and tumor pain; nausea; urge to defecate; and fatigue. Hematologic toxicity was infrequent and mild. ON 01910.Na pharmacokinetics were characterized by a rapid distribution phase (distribution half-life, 1 hour) and a relatively slow elimination phase (elimination half-life, 27 hours). A refractory ovarian cancer patient had an objective response after four cycles and remained progression free for 24 months.
  
  
  CONCLUSIONS
  ON 01910.Na showed a distinct but moderate toxicity pattern. The recommended phase II dose of ON 01910.Na with this schedule of administration is 3,120 mg. Single-agent activity was documented in an ovarian cancer patient.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA. antonio.jimeno@uchsc.edu
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Manoj
authors.initials: M
authors.lastname: Maniar
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D005260:Female; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D005998:Glycine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013450:Sulfones; D000097869:Polo-Like Kinase 1; C507134:ON 01910